Prediction of phenytoin solubility in intravenous admixtures: physicochemical theory.

The application of basic scientific principles to the practical problem of phenytoin precipitation in large volume parenteral solutions is reviewed. The solubility of phenytoin in i.v. admixtures depends on phenytoin's pKa and the i.v. solution pH as well as the admixture volume and the solubility of undissociated phenytoin in that admixture. Equations are derived that predict the solubility of phenytoin in i.v. admixtures, and illustrative examples are presented using the formulas. The effect of storage time on phenytoin solubility is discussed, and the effects of hydroalcoholic solvents (present in commercially available sodium phenytoin injection) and their dilution in aqueous admixtures are considered. Although simple equations can be used to predict the solubility of phenytoin sodium injection in i.v. fluids, the time required for a precipitate to develop cannot be predicted because of the variability in published studies.